期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 51, 期 -, 页码 137-145出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2013.09.005
关键词
Glucokinase activator; Beta-cell proliferation; Glucotoxicity; INS-1 cells; Type 2 diabetes; Apoptosis
资金
- Ministry of Knowledge Economy, Republic of Korea [C-2-1, 500108, 7007618]
- Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Korea [A062260]
- National Research Foundation of Korea [C-2-1] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose-6-phosphate, has a role in regulating insulin secretion and proliferation in beta cells. GK activators (GKAs) have been developed as new therapies for type 2 diabetes. In this study, we evaluated the proliferation and anti-apoptotic actions of YH-GKA, a novel and potent GKA, in INS-1 pancreatic beta-cells. YH-GKA treatment increased cell numbers at 3 mM glucose via upregulation of insulin receptor substrate-2 and subsequent activation of AKT/protein kinase B phosphorylation. YH-GKA also increased beta-catenin and cyclin D2 mRNA expression and inactivated GSK3 beta by increasing phosphorylation. These proliferative effects of YH-GKA were attenuated by IRS-2 downregulation. Moreover, YH-GKA reduced annexin-V-stained cells and expression levels of cleaved poly (ADP-ribose) polymerase and caspase-3 induced by glucotoxicity. YH-GKA inhibited apoptotic signaling via induction of ATP content, mitochondrial membrane potential, and citrate synthase activity and was correlated with changes of the mitochondrial function-related genes. YH-GKA also increased interaction between GK and voltage-dependent anion-selective channel protein. Our results suggest that the novel GKA, YH-GKA, promotes beta cell growth and prevents glucotoxic beta cell apoptosis. Therefore, YH-GKA may provide a therapy that compensates for beta cell loss in patients with type 2 diabetes. (C) 2013 Elsevier B.V. All rights reserved.
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